Visceral Neurophysiology Laboratory

pain, enteric nervous system, nociceptors, colon, peristalsis...

A micrograph displaying immuno-reactive neurons
to calcitonin gene-related peptide (red), and nitric oxide synthase (green) within the myenteric plexus of the mouse colon

Research Summary

Pain is an essential component of life. It is a protective sensation that informs us to avoid harmful situations and tissue damage. Noxious stimuli are vital to tell us when a particular movement or task is putting too much strain (or potential damage) on our bodies. Nociceptors are sensory receptors whose transduction sites respond to potentially damaging (painful) stimuli by sending action potentials to the spinal cord and brain. This process is referred to as nociception.

In skin, there is an extensive knowledge about the different types of sensory nerve endings and which specific types of sensory endings respond to which particular stimuli. This is not the case for internal organs. In fact, very little is known about the different types of sensory endings that innervate any of the internal organs in mammals (such as the GI-tract) and even less is known about how disease states, such as inflammatory bowel disease, cause these nerve endings to become hyperexcitable, leading to increased pain sensations. This is problematic if we are to develop analgesics that selectively target pain fibres to improve quality of life, because it is important to know how and where the nerve endings that detect painful stimuli exist in the peripheral organ. Our striking lack of understanding about which sensory nerves detect pain from any internal organ has largely arisen because of the lack of techniques available to visualize only the nerve endings that detect pain.

Research Projects

Optogenetics to silence pain pathways in the visceral organs

In 2015, we commenced an exciting collaboration with Dr Hongzhen Hu at Washington University, in St. Louis, Mo. USA. This project has been the first to demonstrate that fluorescent light can be used to activate specific populations of enteric neurons that underlie propulsive contractions of the gastrointestinal tract. This very exciting technique will involve implanting wireless light emitting diodes (LEDs) into mammals, for the wireless control of gastrointestinal motility.

Identification of the different types of spinal afferent nociceptors

We have recently developed a new technique, whereby it is possible for the first time, to identify the different types of spinal afferent nerve endings that innervate internal organs. This is of supreme interest to us, because the identity, location, neurochemistry and morphology of the nerve endings that detect pain from internal organs, such as the GI-tract, has been a major unanswered question. The major aims of this project are to identify the sites of innervation of the pain fibres throughout the gastrointestinal tract, bladder and uterus and how these nerve endings are activated with the use of calcium imaging.

We have made a recent breakthrough regarding serotonin (5-HT) in the gut wall. It has long been thought that since antagonists of 5-HT receptors block peristalsis that 5-HT must be an important transmitter underlying the generation of peristalsis. We found recently that total depletion (confirmed with mass spectrometry) of endogenous 5-HT did not block peristalsis. In fact it has very minor effects on peristalsis. Also, we found antagonists of 5-HT receptors still blocked peristalsis every when there was no detectable 5-HT in the gut wall. endogenous 5-HT was not a major player in gut motility.

Real time calcium imaging of the activation of spinal afferent nerve endings

The aims of this project are to characterize the mechanisms by which the nerve endings of spinal afferents transduce nociceptive stimuli into action potentials in the gastrointestinal tract. We use a novel imaging technique, which allows us to visualize activity directly within the spinal afferent endings that detect noxious the major ionic mechanisms underlying their activation.

Recording dynamic changes in intracellular calcium from...

Recording dynamic changes in intracellular calcium from the nerve endings of CGRP expressing sensory fibres in transgenic CGRP alpha reporter miceWe have generated and published development of a novel transgenic mouse that expressed the red fluorescent protein (mCherry) driven by the CGRP alpha promoter. This allows us for the first time to visualise and then record in live tissue from the nerve endings of nociceptive fibres that express the CGRP alpha gene. This is a major new step forward in recording from spinal afferent nerve endings in visceral organs.

Fibre optic high-resolution recordings of motor activities in large intestine

Our laboratory was the first to isolate and record from the isolated whole human colon see (Dinning et al. 2016). This new technique is very exciting because for the first time, we record from the conscious human patient characterize the specific patterns of motor activity that exist in isolated human colon and how these patterns differ in disease states such as ulcerative colitis and Crohn’s disease.

Role of intrinsic nerves in the movement of intestinal content

The gut wall contains a complete network of intrinsic nerves capable of propelling contents along the bowel, without any requirement of nerves originating in the brain or spinal cord. Work in our laboratory aims to understand how intrinsic nerves in the gut wall are activated to cause the contents within the bowel to be propelled from one region to another. Our current research projects, broadly address two fundamental area of interest:
1. mechanisms of activation of spinal afferent pain pathways following colo-rectal distension and in response to intestinal inflammation, and
2. the intrinsic neuronal mechanisms underlying colonic propulsion.

Our broad underlying goal is to determine the mechanisms of activation of intrinsic neural networks, underlying complex propulsive motor patterns in the large intestine (such as the migrating motor complex) and how these neural networks become dysfunctional in a variety of complex disease states. We use a variety of novel techniques, including in vivo and in vitro imaging of intracellular calcium, video imaging and spatio-temporal mapping of the colonic wall movements and EMG recordings from mutant mice that lack visceral pain detection.

The aims of this project are to determine how the loss of intrinsic neurons with age leads to impaired colonic motility and the onset of chronic constipation. We have a colony of spontaneous mutant mice that lack a specific gene responsible for development.

Spencer NJ (2015) Constitutively active 5-HT Receptors: An Explanation of How 5-HT Antagonists Inhibit Gut Motility in Species Where 5-HT is Not an Enteric Neurotransmitter? Frontiers in Cellular Neuroscience, 9:487